Peripheral and Central Inflammatory Signals in the sickness Response This application investigates the hypothesis that inflammation-induced negative energy balance is mediated by mechanisms dependent on cytokine signaling pathways within brain tissue. Systemic inflammatory conditions cause marked weight loss yet the necessity of cytokines in 'sickness'remains unclear and the interaction between inflammation and neuronal regulators of energy balance remains unknown. The Specific Aims seek to determine the role of key inflammatory pathways in mediating the 'sickness response'by determining 1) whether inflammatory signals in brain tissue are necessary and sufficient to mediate the sickness response', and whether inflammatory signaling in neurons and endothelial cells is necessary to cause 'sickness', and 2) whether hypothalamic melanocortin signaling is necessary for 'sickness'to occur. To accomplish these objectives, studies are proposed using a variety of mutant mouse models to evaluate 'sickness'using methods established in the laboratories of the applicant and the Consultants participating in this proposal, including determining energy intake and expenditure, quantifying hypothalamic and circulating cytokines and bone marrow transplantation to alter the genotype of circulating immune cells. These aims make an important contribution to understanding the mechanism whereby inflammation affects energy balance and may identify potential therapies for disorders ranging from obesity to chronic wasting illnesses.